High concentration topical insecticide containing pyriproxyfen

ABSTRACT

A topical insecticide is provided which can be safe to use and avoids many common deleterious side effects of conventional topical insecticides. In one preferred embodiment of the invention, the active ingredient of the insecticide formulation is an amine derivative, having a nitro-methylene group, a nitroamino group or a cyanoamino group, which can be formulated to have low toxicity and excellent insecticidal activity. One particularly suitable insecticide is 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran), an aldulticide that will kill adult fleas combined with pyriproxyfen.

BACKGROUND OF INVENTION

[0001] The invention relates generally to insecticides and moreparticularly to a topical insecticide, such as one suitable to use onhouse pets such as cats and dogs.

[0002] The infestation of animals with fleas, ticks, flies and the likeis highly undesirable. Accordingly, it has become common to administerboth topical and internal insecticides to livestock and pets. Topicalapplications can be desirable, in that many insecticides are acceptablysafe when used topically, but not when used internally.

[0003] Various topical insecticides have drawbacks. Some require a largevolume to be applied to the animal. This can cause considerable mess andcan lead to an unpleasant smell. Also, when the animal is a house pet,there is a further complication in that the insecticide should be safefor human contact. It should also not lead to staining of furniture,carpeting and the like. Finally, even if safe, topical insecticides forhouse pets should not be irritating or lead to rashes, hair loss orexhibit other unpleasant side effects.

[0004] Accordingly, it is desirable to provide an improved topicalinsecticide, which overcomes drawbacks of the prior art.

SUMMARY OF THE INVENTION

[0005] Generally speaking, in accordance with the invention, a topicalinsecticide is provided which can be safe to use and avoids many commondeleterious side effects of conventional topical insecticides. In onepreferred embodiment of the invention, the active ingredient of theinsecticide formulation is an amine derivative, having a nitro-methylenegroup, a nitroamino group or a cyanoamino group, which can be formulatedto have low toxicity and excellent insecticidal activity. Activeingredients of insecticides and their method of formation in accordancewith the preferred embodiments of the invention are discussed in U.S.Pat. Nos. 5,532,365 and 5,434,181, the contents of which areincorporated herein by reference. One particularly suitable insecticideis 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine(dinotefuran). Dinotefuran is an aldulticide that will kill adult fleas.

[0006] In one preferred embodiment of the invention, the active portionof the insecticide formulation comprises(tetrahydro-3-furanyl)methylamine derivatives of following formula (1).

[0007] Active ingredients and insecticides in accordance with preferredembodiments of the invention are generally available as crystals andsolids. Therefore, they need to be dissolved or otherwise put into aliquid form for use as topical spot products on animals. Topical spotproducts are more advantageous if the amount of liquid applied can beminimized. This must be balanced with the need for appropriate dosage toachieve the desired insecticidal effect. Therefore, it is desirable touse a solvent that will allow the solubilization of a high concentrationof insecticide.

[0008] It is also desirable that the resulting formulation be stable(i.e., no crystallization) when stored at 0° F. and 40° F. for 1 month,which is important because these conditions can be met in commerce. Thecrystallization would reduce the amount of insecticide in solution andreduce the efficacy of the solution applied to the animal.

[0009] Phenyl methanol, is an alcohol, also known as benzyl alcohol, andis a liquid, somewhat soluble in water. It is routinely used inperfumes, flavors, photographic developers, dyes, films and inks and hasother uses. It was surprisingly discovered that a relatively highconcentration of the dinotefuran could be solubilized in phenylmethanol.

[0010] Pyriproxyfen is an insecticide that acts as an insect growthregulator that prevents flea eggs from hatching. It was unexpectedlydetermined that pyriproxyfen can act as a solvent for the aminederivative insecticides such as dinotefliran, discussed above. Forexample, the addition of pyriproxyfen to the dinotefuran formulationswith phenyl methanol allowed the preparation of more highly concentratedsolutions of dinotefuran that do not crystallize at 0° F.

[0011] In one aspect of the current invention, the dinotefuran isdissolved in solvent containing pyriproxyfen to a concentration range of5-25%, more preferably 9-20% and most preferably about 12.5 to 19.2%,with 15.7% as a preferred example. All percentages, unless otherwiseevident, are on a weight basis.

[0012] Accordingly, it is an object of the invention to provide animproved topical insecticide, which overcomes drawbacks of the priorart.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The novel (tetrahydro-3-furanyl)methylamine derivatives of theformula (1) have an excellent insecticidal activity even in the absenceof a pyridylmethyl group or a thiazolylmethyl group in their molecularstructure. According to the present invention, there are provided(tetrahydro-3-furanyl)methylamine derivatives represented by formula(1), where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ represent each a hydrogen atomor an alkyl group having from 1 to 4 carbon atoms; R₁ represents ahydrogen atom, an alkyl group having from 1 to 5 carbon atoms, analkenyl group having 3 carbon atoms, a benzyl group, an alkoxyalkylgroup having from 2 to 4 carbon atoms (in its whole group), analkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonyl group having from 1 to 6 carbon atoms,an alkenylcarbonyl group having from 2 to 3 carbon atoms, acycloalkylcarbonyl group having from 3 to 6 carbon atoms, a benzoylgroup, a benzoyl group substituted by alkyl group(s) having from 1 to 4carbon atoms, a benzoyl group substituted by halogen atom(s), a2-furanylcarbonyl group or an N,N-dimethylcarbamoyl group; R₂ representsa hydrogen atom, an amino group, a methyl group, an alkylamino grouphaving from 1 to 5 carbon atoms, a di-substituted alkylamino grouphaving from 2 to 5 carbon atoms (in its whole group), a 1-pyrrolidinylgroup, an alkenylamino group having 3 carbon atoms, an alkynylaminogroup having 3 carbon atoms, a methoxyamino group, an alkoxyalkylaminogroup having from 2 to 4 carbon atoms (in its whole group), a methylthiogroup or —N(Y₁)Y₂ (where Y₁ represents an alkyloxycarbonyl group havingfrom 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonylgroup having from 1 to 6 carbon atoms, an alkenylcarbonyl group havingfrom 2 to 3 carbon atoms, a cycloalkylcarbonyl group having from 3 to 6carbon atoms, a benzoyl group, a benzoyl group substituted by alkylgroup(s) having from 1 to 4 carbon atoms, a benzoyl group substituted byhalogen atom(s), a 2-furanylcarbonyl group, an N,N-dimethylcarbamoylgroup, a (tetrahydro-3-furanyl)methyl group or a benzyl group, and Y₂represents a hydrogen atom or an alkyl group having from 1 to 5 carbonatoms); and Z represents ═N—NO₂, ═CH—NO₂ or ═N—CN; insecticidescontaining the derivatives as an effective ingredient; and intermediatesfor producing the compounds of the formula (1) represented by a formula(2):

[0014] where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ represent each a hydrogenatom or an alkyl group having from 1 to 4 carbon atoms; R₁₀ representsan alkyl group having from 1 to 5 carbon atoms or a benzyl group; andR₁₁ represents an alkyl group having from 1 to 5 carbon atoms or abenzyl group.

[0015] The novel (tetrahydro-3-furanyl)methylamine derivatives of theformula (1) and formula (2) according to the invention are excellentcompounds having a high insecticidal power and broad insecticidalspectrum. Further, agricultural chemicals containing the novel(tetrahydro-3-furanyl)methylamine derivatives of the formula (1) and (2)according to the invention have outstanding characteristics asinsecticides and hence are useful.

[0016] Specific examples of the alkyl group for X₁, X₂, X₃, X₄, X₅, X₆and X₇ in the above formulae (1) and (2) include a methyl group, anethyl group, an n-propyl group, an iso-propyl group, a tert-butyl group,and the like, preferably a methyl group.

[0017] Specific examples of the alkyl group for R₁ include a methylgroup, an ethyl group, an n-propyl group, an iso-propyl group, ann-butyl group, an iso-butyl group, a sec-butyl group, a tert-butylgroup, an n-pentyl group, and the like.

[0018] Specific examples of the alkenyl group for R₁ include a1-propenyl group, a 2-propenyl group, and the like.

[0019] Specific examples of the alkoxyalkyl group for R₁ include amethoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, aniso-propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, andthe like.

[0020] Specific examples of the alkyloxycarbonyl group for R₁ include amethyloxycarbonyl group, an ethyloxycarbonyl group, ann-propyloxycarbonyl group, an iso-propyloxycarbonyl group, and the like.

[0021] Specific examples of the alkylcarbonyl group for R₁ include amethylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group,an iso-propylcarbonyl group, an n-butylcarbonyl group, aniso-butylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonylgroup, an n-pentylcarbonyl group, an n-hexylcarbonyl group, and thelike.

[0022] Specific examples of the alkenylcarbonyl group for R₁ include avinylcarbonyl group, a 1-methylvinylcarbonyl group, and the like.

[0023] Specific examples of the cycloalkylcarbonyl group for R₁ includea cyclopropylcarbonyl group, a cyclobutylcarbonyl group, acyclopentylcarbonyl group, a cyclohexylcarbonyl group, and the like.

[0024] Specific examples of the benzoyl group substituted by alkylgroup(s) for R₁ include a 2-methylbenzoyl group, a 3-methylbenzoylgroup, a 4-methylbenzoyl group, a 4-tert-butylbenzoyl group, and thelike.

[0025] Specific examples of the benzoyl group substituted by halogenatom(s) for R1 include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group,a 4-chlorobenzoyl group, a 3,4-dichloro-benzoyl group, a 4-fluorobenzoylgroup, and the like.

[0026] Although R₁ can take various substituents as described above, itis preferably a hydrogen atom, an alkylcarbonyl group having from 1 to 4carbon atoms or a cyclopropylcarbonyl group.

[0027] Specific examples of the alkylamino group for R₂ include amethylamino group, an ethylamino group, an n-propyl-amino group, aniso-propylamino group, an n-butylamino group, an iso-butylamino group, asec-butylamino group, a tert-butylamino group, an n-pentylamino group,and the like, preferably a methylamino group.

[0028] Specific examples of the di-substituted alkylamino group for R₂include a dimethylamino group, a diethylamino group, anN-methyl-N-ethylamino group, an N-methyl-N-n-propylamino group, anN-methyl-N-n-butylamino group, and the like, preferably a dimethylaminogroup.

[0029] Specific examples of the alkenylamino group for R₂ include a1-propenylamino group, a 2-propenylamino group, and the like.

[0030] Specific examples of the alkynylamino group for R₂ include apropargylamino group, and the like.

[0031] Specific examples of the alkoxyalkylamino group for R₂ include amethoxymethylamino group, an ethoxymethylamino group, ann-propoxymethylamino group, an iso-propoxymethylamino group, amethoxyethylamino group, an ethoxyethylamino group, and the like.

[0032] Specific examples of the alkyloxycarbonyl group denoted by Y₁ forR₂ include a methyloxycarbonyl group, an ethyloxy-carbonyl group, ann-propyloxycarbonyl group, an iso-propyloxy-carbonyl group, and thelike.

[0033] Specific examples of the alkylcarbonyl group denoted by Y₁ for R₂include a methylcarbonyl group, an ethylcarbonyl group, ann-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonylgroup, an isobutylcarbonyl group, a sec-butyl-carbonyl group, atertbutylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonylgroup, and the like, preferably a methylcarbonyl group, an ethylcarbonylgroup, an n-propylcarbonyl group, an iso-propylcarbonyl group, ann-butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonylgroup and a tert-butylcarbonyl group.

[0034] Specific examples of the alkenylcarbonyl group denoted by Y₁ forR₂ include a vinylcarbonyl group, a 1-methyl-vinylcarbonyl group, andthe like.

[0035] Specific examples of the cycloalkylcarbonyl group denoted by Y₁for R₂ include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group,a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, and the like,preferably a cyclopropyl-carbonyl group.

[0036] Specific examples of the benzoyl group substituted byalkylgroup(s) denoted by Y₁ for R₂ include a 2-methylbenzoyl group, a3-methylbenzoyl group, a 4-methylbenzoyl group, a 4-tert-butylbenzoylgroup, and the like.

[0037] Specific examples of the benzoyl group substituted by halogenatom(s) denoted by Y₁ for R₂ include a 2-chlorobenzoyl group, a3-chlorobenzoyl group, a 4-chlorobenzoyl group, a 3,4-dichlorobenzoylgroup, a 4-fluoro benzoyl group, and the like.

[0038] Specific examples of the alkyl group denoted by Y₂ for R₂ includea methyl group, an ethyl group, an n-propyl group, an iso-propyl group,an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butylgroup, an n-pentyl group, and the like, preferably a methyl group.

[0039] In the formula (1), compounds in which R₁ and Y₁ are concurrentlyan alkylcarbonyl group having from 1 to 4 carbon atoms or acyclopropylcarbonyl group are preferred from the viewpoint of bothinsecticidal activity and production method.

[0040] In the development of a formulation for use on animals, there areseveral parameters that must be considered. These are:

[0041] (a) Concentration high enough to minimize the volume of thetopical applied to the animal (one would not want to put 20 ml, e.g.,onto a small cat).

[0042] (b) The formulation should be stable for one month at 130° F.,110° F., 40° F., room temperature and 0° F. This helps ensure that theformulation remains stable under the conditions that it could meet incommerce.

[0043] (c) Safe to use on the animal—particularly non-irritating sincethe product is applied to the skin. Also safe if ingested by the animal;ingestion can occur when cats groom themselves.

[0044] (d) Safe to use by the consumer.

[0045] (e) Efficacious in use—should kill greater than 90% of the fleasup to 28 days.

[0046] (f) Efficacy would be reduced if crystallization occurred in thepackage.

[0047] (g) Needs to be aesthetically pleasing—“no oily drop” on theanimal when applied.

[0048] (h) Fast drying to reduce the chance of the animal shaking offthe liquid thereby reducing efficacy.

[0049] (i) Microbiologically stable.

[0050] The above-referenced patents recognize different possiblesolvents, but do not provide information on how to formulate insecticidein a non-irritating manner. No examples were given in which thecompounds were used on animals. Additionally, in all of the examplesgiven the compounds were dissolved into solvents that are undesirable touse on animals. Specifically, acetone, used in all but one of theexamples, is very irritating by both inhalation and skin contact, due tode-fatting action on skin and mucous membranes. It is also veryirritating to the eyes. Accordingly, there is a need to develop adifferent solvent for these compounds that can be used on animals. Thepresent formulation satisfies the parameters detailed above.

[0051] In one aspect of the current invention, the dinotefuran isdissolved in solvent containing pyriproxyfen to a concentration range of5-25%, more preferably 9-20% and most preferably about 12.5 to 19.2%,with 15.7% as a preferred example. All percentages, unless otherwiseevident, are on a weight basis. Pyriproxyfen is advantageously includedas over 0.1%, advantageously about 0.1 to 3%.

[0052] The following examples are given for purposes of illustrationonly and are not intended to be construed in a limiting manner.

EXAMPLE 1 Preparation of1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (Dinotefuran)

[0053] A mixture comprising 10.0 g of (tetrahydro-3-furanyl)methanol,29.5 g of trifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200ml of dichloromethane was stirred for an hour at room temperature. Waterwas poured into the reaction solution to separate the organic layer,which was washed with 1 N hydrochloric acid, water and a saturatedsaline solution, dried, and concentrated to obtain 20 g of3-tetrahydro-furanylmethyl triflate. 3.25 g of 60% sodium hydride wereadded to 12.5 g of 1,5-dimethyl-2-nitroiminohexahydro-1,3,5-triazine and60 ml of DMF at room temperature, followed by stirring for an hour. 20.0g of the 3-tetrahydrofuranylmethyl triflate were added thereto, and themixture was stirred at 50° C. for 2 hours. After cooling the mixture toroom temperature, 50 ml of 2N hydrochloric acid were added thereto,followed by stirring at 50° C. for 2 hours. The resultant mixture wasneutralized with sodium bicarbonate and extracted with dichloromethane,and the extract was dried and concentrated. The residue thus obtainedwas purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/1) to obtain 7.8 g of1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine(dinotefuran).

EXAMPLE 2 Preparation of Insecticide Formulation Containing Dinotefuran,Ethanol and Water

[0054] 5 g (i.e., 5.6% (weight/weight)) of dinotefuran was dissolvedinto 100 ml of a mixture comprising 70% ethanol and 30% water. Theresulting mixture can be spot applied to companion animals, such as dogsand cats and will kill fleas, ticks and other insects.

EXAMPLE 3 Preparation of Insecticide Formulation Containing Dinotefuranand Phenyl Methanol

[0055] 15 g (i.e., 12.5% (weight/weight)) of dinotefuran was dissolvedinto 100 ml of phenyl methanol. The resulting solution can be spotapplied to companion animals, such as dogs and cats and will kill fleas,ticks and other insects.

EXAMPLE 4 Preparation of Insecticide Formulation Containing Dinotefuran,Pyriproxyfen and Phenyl Methanol

[0056] 20 g of dinotefuran was added to 100 ml phenyl methanol withstirring until it dissolves. 3 g of pyriproxyfen was added to thesolution with stirring to produce a clear, homogeneous solution.

EXAMPLE 5 Preparation of Insecticide Formulation Containing Dinotefuran,Pyriproxyfen and Phenyl Methanol

[0057] 25 g of dinotefuran was added to 100 ml phenyl methanol withstirring until it dissolved. 1 g of pyriproxyfen was added to thesolution with stirring to produce a clear, homogeneous solution of highinsecticide concentration.

[0058] The resulting solution can be spot applied to companion animals,such as dogs and cats and will kill fleas, ticks and other insects.

EXAMPLE 6 Stability of Dinotefuran/Pyriproxyfen Formulations

[0059] Table 1 demonstrates that an approximate 50% increase inconcentration can be achieved for dinotefuran by including pyriproxyfenat low levels in the formulation based on the criterion of no crystalformation at 0° F. during a 1 month period. TABLE 1 FormulationStability Studies (% are w/w) Dinotefuran Pyriproxyfen Phenyl MethanolStable 12.5 0 87.5 Yes 14.7 0 85.3 No* 15.7 2.4 81.9 Yes 15.9 0.8 83.3Yes 19.2 0.8 80.0 Yes

EXAMPLE 7 In Vivo Activity of a Flea Dermal Treatment Against the CatFlea (Ctenocephalides felis) on Cats

[0060] Eighteen cats were separated into three groups each containing 6cats. Group 1 (6 cats each weighing 9 lbs. or less) remained untreatedas Non-Treated Controls. Group 2 (6 cats each over 9 lbs.) were treatedwith 3.4 ml of the dinotefuran insecticide formulation (5.71% w/w).Group 3 (6 cats each weighing 9 lbs. or less) were treated with 1.5 mlof the dinotefuran insecticide formulation (5.71% w/w).

[0061] Approximately 18 hours prior to treatment the cats were infestedwith 100 cat fleas (Ctenocephalides felis) which were applied to theanimal's back. Cats in Groups 2 and 3 were then treated with theindicated volume of insecticide by dispensing the liquid at skin levelbetween the shoulder blades. Flea counts were taken at day 1 (i.e., 24hours post-treatment), day 8, day 15, day 22 and day 29. Cats werere-infested with 100 fleas on days 7, 14, 21, and 28. To determine theefficacy of the dermal treatment, the number of fleas found on treatedcats was compared to the number of fleas found on untreated cats.Percent reduction was determined as follows and the results aresummarized in Table 2: $\frac{\begin{matrix}{{{Mean}\quad {Number}\quad {of}\quad {fleas}\quad {on}\quad {Untreated}\quad {Cats}} -} \\{{Mean}\quad {Number}\quad {of}\quad {fleas}\quad {on}\quad {Treated}\quad {Cats}}\end{matrix}}{{Mean}\quad {Number}\quad {of}\quad {fleas}\quad {on}\quad {Untreated}\quad {Cats}} \times 100\quad \%$

[0062] As shown in Table 2 the results demonstrate that the dosages usedon Groups 2 and 3 are both effective at reducing the number of adultfleas on cats through at least 29 days and thus are effective as a onemonth dermal treatment. TABLE 2 Controlled Percent Reduction in FleaPopulation Day 1 Day 8 Day 15 Day 22 Day 29 Control 0 0 0 0 0 Group 1Group 2 100 100 99 99 96 Group 3 100 98 95 95 91

[0063] It will thus be seen that the objects set forth above, amongthose made apparent from the preceding description, are efficientlyattained and, since certain changes may be made in carrying out theabove method and in the composition set forth without departing from thespirit and scope of the invention, it is intended that all mattercontained in the above description shall be interpreted as illustrativeand not in a limiting sense.

[0064] It is also to be understood that the following claims areintended to cover all of the generic and specific features of theinvention herein described and all statements of the scope of theinvention which, as a matter of language, might be said to falltherebetween.

[0065] Particularly it is to be understood that in said claims,ingredients or compounds recited in the singular are intended to includecompatible mixtures of such ingredients wherever the sense permits.

What is claimed is:
 1. An insecticide formulated by dissolving aninsecticidably effective amount of an insecticidal(tetrahydro-3-furanyl) methylamine derivative in an effective amount ofa solvent component comprising sufficient pyriproxyfen to increase thesolvency of the solvent component without the pyriproxyfen and toincrease the effectiveness of the insecticide without the pyriproxyfen.2. The insecticide of claim 1, wherein said insecticidal derivative isdinotefuran.
 3. The insecticide of claim 2, wherein said solventcomponent comprises phenyl methanol.
 4. The insecticide of claim 2,wherein said solvent component comprises ethanol.
 5. The insecticide ofclaim 1, wherein said insecticidal derivative is dissolved in theformulation to a concentration of about 5 to 25%.
 6. The insecticide ofclaim 3, wherein said insecticidal derivative is dissolved in theformulation to a concentration of about 9 to 20%.
 7. The insecticide ofclaim 4, wherein said insecticidal derivative is dissolved in theformulation to a concentration of about 9 to 20%.
 8. The insecticide ofclaim 5, comprising over 0.1% pyriproxyfen.
 9. The insecticide of claim5, comprising about 0.1 to 3% pyripoxyfen.
 10. The insecticide of claim6, comprising about 0.1 to 3% pyripoxyfen.
 11. The insecticide of claim1, wherein the formulation is not irritating to dogs or cats and iseffective to kill fleas with applications of less than 20 ml to a cat.12. The insecticide of claim 2, wherein the formulation is notirritating to dogs or cats and is effective to kill fleas withapplications of less than 20 ml to a cat.
 13. The insecticide of claim3, wherein the formulation is not irritating to dogs or cats and iseffective to kill fleas with applications of less than 20 ml to a cat.14. The insecticide of claim 4, wherein the formulation is notirritating to dogs or cats and is effective to kill fleas withapplications of less than 20 ml to a cat.
 15. A method of controllinginsect infestation in animals, comprising dissolving dinotefuran in asolvent mixture comprising pyriproxyfen and applying an insecticidablyeffective amount of the solution to an animal.
 16. The method of claim15, wherein the animal is a cat or a dog.
 17. The method of claim 16,wherein the insect is a flea.
 18. A method of preparing an insecticide,comprising dissolving an insecticide in a composition comprisingpyriproxyfen, wherein at least a portion of the insecticide is dissolvedby the pyriproxyfen.